PD-1/PD-L1 Interaction Regulates BCL2, KI67, BAX, and CASP3, Altering Proliferation, Survival, and Apoptosis in Acute Myeloid Leukemia
-
Mojdeh Soltani
,
Mahshid Vosoughi
,
Mazdak Ganjalikhani-Hakemi
,
Hoorieh Shapoorian
,
Pezhman Beshkar
,
Nahid Eskandari
,
Behrooz Ghezelbash
Abstract
Programmed death ligand‑1 (PD‑L1) is a pivotal inhibitory checkpoint ligand known to induce T-cell exhaustion via interaction with the programmed death‑1 (PD‑1) receptor. Beyond this, PD-L1’s intrinsic signaling pathways within cancer cells warrant further exploration. This study aims to elucidate the effect of PD-L1 stimulation on the proliferation, survival, and apoptosis of acute myeloid leukemia (AML) cell lines.
Two human AML cell lines, HL-60 and THP-1 were cultured and treated with phorbol 12-myristate 13-acetate (PMA) to induce PD-L1overexpression. Post-treatment PD-L1 expression was confirmed via flow cytometry. Subsequently, cell surface PD-L1 was stimulated using a recombinant PD-1, 24 hours post-PMA treatment. The expression alterations in pivotal genes including BCL2, MKI67, BAX, and CASP3 were monitored using quantitative real-time polymerase chain reaction 24 and 48 hours post-treatment. Additionally, annexin-V through flow cytometry.
Findings reveal that PD-L1 stimulation augments AML cell proliferation and survival by enhancing MKI67 and BCL2 expressions while concurrently inhibiting cell apoptosis due to decreased BAX and CASP3 expression following PD-L1 stimulation. Notably, stimulated cells expressed exhibited reduced annexin-V compared to control cells.
This study underscores that PD-L1 stimulation fosters AML cell proliferation and survival while impeding cell apoptosis. The results hold potential implications for targeting PD-L1 in AML treatment strategies.
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3. Soltani M, Zhao Y, Xia Z, Hakemi MG, Bazhin A. The importance of cellular metabolic pathways in pathogenesis and selective treatments of hematological malignancies. Front Oncol. 2021:4665.
4. Zhang S, Liu M, Yao Y, Yu B, Liu H. Targeting LSD1 for acute myeloid leukemia (AML) treatment. Pharmacol Res. 2021;164:105335.
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6. Fouladseresht H, Ziaee SM, Erfani N, Doroudchi M. Serum Levels of APRIL Increase in Patients with Glioma, Meningioma and Schwannoma. Asian Pac J Cancer Prev. 2019;20(3):751-6.
7. Chen C, Liang C, Wang S, Chio CL, Zhang Y, Zeng C, et al. Expression patterns of immune checkpoints in acute myeloid leukemia. J Hematol Oncol. 2020;13(1):28.
8. Dong P, Xiong Y, Yue J, Hanley SJ, Watari H. Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment: beyond immune evasion. Front Oncol. 2018;8:386.
9. Escors D, Gato-Cañas M, Zuazo M, Arasanz H, García-Granda MJ, Vera R, et al. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct. Target. 2018;3(1):1-9.
10. Rayati Damavandi A, Zolfaghari Baghbadorani P, Kardideh B, Fouladseresht H, Golabi M, Ghezelbash B, et al. The Association of Programmed Death 1 Gene Polymorphisms of PD1.3 G/A and PD1.5 C/T with Risk of COVID-19 in an Iranian Population: A Case-Control Study. Viral immunol. 2022.
11. Fouladseresht H, Ghamar Talepoor A, Eskandari N, Norouzian M, Ghezelbash B, Beyranvand MR, et al. Potential Immune Indicators for Predicting the Prognosis of COVID-19 and Trauma: Similarities and Disparities. Front Immunol. 2021;12:785946.
12. Dong Y, Han Y, Huang Y, Jiang S, Huang Z, Chen R, et al. PD-L1 Is Expressed and Promotes the Expansion of Regulatory T Cells in Acute Myeloid Leukemia. Front Immunol. 2020;11(1710).
13. Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994;54(12):3131-5.
14. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4):609-19.
15. Soltani M, Ghanadian M, Ghezelbash B, Shokouhi A, Zamyatnin AA, Jr., Bazhin AV, et al. PD-L1 stimulation can promote proliferation and survival of leukemic cells by influencing glucose and fatty acid metabolism in acute myeloid leukemia. BMC cancer. 2023;23(1):447.
16. Cui Y, Li Y, Li X. The impact of PD-L1 on glucose metabolism of lung adenocarcinoma cells. Soc Nuclear Med. 2018.
17. Ghebeh H, Tulbah A, Mohammed S, ElKum N, Amer SMB, Al‐Tweigeri T, et al. Expression of B7‐H1 in breast cancer patients is strongly associated with high proliferative Ki‐67‐expressing tumor cells. Int J Cancer. 2007;121(4):751-8.
18. Takada K, Toyokawa G, Tagawa T, Kohashi K, Akamine T, Takamori S, et al. Association between PD-L1 expression and metabolic activity on 18F-FDG PET/CT in patients with small-sized lung cancer. Anticancer Res. 2017;37(12):7073-82.
19. Wang Z, Chen J, Wang M, Zhang L, Yu L. One Stone, Two Birds: The Roles of Tim-3 in Acute Myeloid Leukemia. Front Immunol. 2021;12:618710.
20. Lai CY, Tseng PC, Chen CL, Satria RD, Wang YT, Lin CF. Different Induction of PD-L1 (CD274) and PD-1 (CD279) Expression in THP-1-Differentiated Types 1 and 2 Macrophages. J Inflamm Res. 2021;14:5241-9.
21. Zeng C, Wang W, Yu X, Yang L, Chen S, Li Y. Pathways related to PMA-differentiated THP1 human monocytic leukemia cells revealed by RNA-Seq. Sci. China Life Sci. 2015;58(12):1282-7.
22. Ducker P, Huning S, Rohde S, Lorenzen J, Nashan D. [Merkel cell carcinoma in chronic lymphocytic leukemia : Successful treatment with PD-L 1 inhibition, avelumab and chlorambucil]. Hautarzt. 2020;71(7):553-6.
23. Geduk A, Atesoglu EB, Mehtap O, Demirsoy ET, Menguc MU, Tarkun P, et al. Programmed Cell Death Ligand 1 Expression Level and Prognostic Significance in Acute Myeloid Leukemia Indian J. Hematol. Blood Transfus. 2022:1-9.
24. Hudson K, Cross N, Jordan-Mahy N, Leyland R. The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment. Front Immunol. 2020;11:2362.
25. Siddiqui WA, Ahad A, Ahsan H. The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol. 2015;89(3):289-317.
26. Liu L, Cheng X, Yang H, Lian S, Jiang Y, Liang J, et al. BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion. Mol Cancer. 2022;21(1):59.
27. Fayed EA, Gohar NA, Farrag AM, Ammar YA. Upregulation of BAX and caspase-3, as well as downregulation of Bcl-2 during treatment with indeno[1,2-b]quinoxalin derivatives, mediated apoptosis in human cancer cells. Arch Pharm (Weinheim). 2022;355(5):e2100454.
28. Mestrum SGC, Cremers EMP, de Wit NCJ, Drent RJM, Ramaekers FCS, Hopman AHN, et al. Integration of the Ki-67 proliferation index into the Ogata score improves its diagnostic sensitivity for low-grade myelodysplastic syndromes. Leuk Res. 2022;113:106789.
29. Vesterinen T, Saila J, Blom S, Pennanen M, Leijon H, Arola J. Automated assessment of Ki-67 proliferation index in neuroendocrine tumors by deep learning. APMIS. 2022;130(1):11-20.
30. Yan J, Xue X, Gao C, Guo Y, Wu L, Zhou C, et al. Predicting the Ki-67 proliferation index in pulmonary adenocarcinoma patients presenting with subsolid nodules: construction of a nomogram based on CT images. Quant Imaging Med Surg. 2022;12(1):642-52.
31. Wang F, Yang L, Xiao M, Zhang Z, Shen J, Anuchapreeda S, et al. PD-L1 regulates cell proliferation and apoptosis in acute myeloid leukemia by activating PI3K-AKT signaling pathway. Sci Rep. 2022;12(1):11444.
32. Wang F, Yang L, Xiao M, Zhang Z, Shen J, Anuchapreeda S, et al. PD-L1 regulates cell proliferation and apoptosis in acute myeloid leukemia by activating PI3K-AKT signaling pathway. Sci Rep. 2022;12(1):1-12.
33. Amornsupak K, Thongchot S, Thinyakul C, Box C, Hedayat S, Thuwajit P, et al. HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells. BMC Cancer. 2022;22(1):578.
34. Li J, Chen L, Xiong Y, Zheng X, Xie Q, Zhou Q, et al. Knockdown of PD-L1 in human gastric cancer cells inhibits tumor progression and improves the cytotoxic sensitivity to CIK therapy. Cell. Physiol Biochem. 2017;41(3):907-20.
2. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-52.
3. Soltani M, Zhao Y, Xia Z, Hakemi MG, Bazhin A. The importance of cellular metabolic pathways in pathogenesis and selective treatments of hematological malignancies. Front Oncol. 2021:4665.
4. Zhang S, Liu M, Yao Y, Yu B, Liu H. Targeting LSD1 for acute myeloid leukemia (AML) treatment. Pharmacol Res. 2021;164:105335.
5. Yilmaz M, Wang F, Loghavi S, Bueso-Ramos C, Gumbs C, Little L, et al. Late relapse in acute myeloid leukemia (AML): clonal evolution or therapy-related leukemia? Blood Cancer J. 2019;9(2):7.
6. Fouladseresht H, Ziaee SM, Erfani N, Doroudchi M. Serum Levels of APRIL Increase in Patients with Glioma, Meningioma and Schwannoma. Asian Pac J Cancer Prev. 2019;20(3):751-6.
7. Chen C, Liang C, Wang S, Chio CL, Zhang Y, Zeng C, et al. Expression patterns of immune checkpoints in acute myeloid leukemia. J Hematol Oncol. 2020;13(1):28.
8. Dong P, Xiong Y, Yue J, Hanley SJ, Watari H. Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment: beyond immune evasion. Front Oncol. 2018;8:386.
9. Escors D, Gato-Cañas M, Zuazo M, Arasanz H, García-Granda MJ, Vera R, et al. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct. Target. 2018;3(1):1-9.
10. Rayati Damavandi A, Zolfaghari Baghbadorani P, Kardideh B, Fouladseresht H, Golabi M, Ghezelbash B, et al. The Association of Programmed Death 1 Gene Polymorphisms of PD1.3 G/A and PD1.5 C/T with Risk of COVID-19 in an Iranian Population: A Case-Control Study. Viral immunol. 2022.
11. Fouladseresht H, Ghamar Talepoor A, Eskandari N, Norouzian M, Ghezelbash B, Beyranvand MR, et al. Potential Immune Indicators for Predicting the Prognosis of COVID-19 and Trauma: Similarities and Disparities. Front Immunol. 2021;12:785946.
12. Dong Y, Han Y, Huang Y, Jiang S, Huang Z, Chen R, et al. PD-L1 Is Expressed and Promotes the Expansion of Regulatory T Cells in Acute Myeloid Leukemia. Front Immunol. 2020;11(1710).
13. Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994;54(12):3131-5.
14. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4):609-19.
15. Soltani M, Ghanadian M, Ghezelbash B, Shokouhi A, Zamyatnin AA, Jr., Bazhin AV, et al. PD-L1 stimulation can promote proliferation and survival of leukemic cells by influencing glucose and fatty acid metabolism in acute myeloid leukemia. BMC cancer. 2023;23(1):447.
16. Cui Y, Li Y, Li X. The impact of PD-L1 on glucose metabolism of lung adenocarcinoma cells. Soc Nuclear Med. 2018.
17. Ghebeh H, Tulbah A, Mohammed S, ElKum N, Amer SMB, Al‐Tweigeri T, et al. Expression of B7‐H1 in breast cancer patients is strongly associated with high proliferative Ki‐67‐expressing tumor cells. Int J Cancer. 2007;121(4):751-8.
18. Takada K, Toyokawa G, Tagawa T, Kohashi K, Akamine T, Takamori S, et al. Association between PD-L1 expression and metabolic activity on 18F-FDG PET/CT in patients with small-sized lung cancer. Anticancer Res. 2017;37(12):7073-82.
19. Wang Z, Chen J, Wang M, Zhang L, Yu L. One Stone, Two Birds: The Roles of Tim-3 in Acute Myeloid Leukemia. Front Immunol. 2021;12:618710.
20. Lai CY, Tseng PC, Chen CL, Satria RD, Wang YT, Lin CF. Different Induction of PD-L1 (CD274) and PD-1 (CD279) Expression in THP-1-Differentiated Types 1 and 2 Macrophages. J Inflamm Res. 2021;14:5241-9.
21. Zeng C, Wang W, Yu X, Yang L, Chen S, Li Y. Pathways related to PMA-differentiated THP1 human monocytic leukemia cells revealed by RNA-Seq. Sci. China Life Sci. 2015;58(12):1282-7.
22. Ducker P, Huning S, Rohde S, Lorenzen J, Nashan D. [Merkel cell carcinoma in chronic lymphocytic leukemia : Successful treatment with PD-L 1 inhibition, avelumab and chlorambucil]. Hautarzt. 2020;71(7):553-6.
23. Geduk A, Atesoglu EB, Mehtap O, Demirsoy ET, Menguc MU, Tarkun P, et al. Programmed Cell Death Ligand 1 Expression Level and Prognostic Significance in Acute Myeloid Leukemia Indian J. Hematol. Blood Transfus. 2022:1-9.
24. Hudson K, Cross N, Jordan-Mahy N, Leyland R. The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment. Front Immunol. 2020;11:2362.
25. Siddiqui WA, Ahad A, Ahsan H. The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol. 2015;89(3):289-317.
26. Liu L, Cheng X, Yang H, Lian S, Jiang Y, Liang J, et al. BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion. Mol Cancer. 2022;21(1):59.
27. Fayed EA, Gohar NA, Farrag AM, Ammar YA. Upregulation of BAX and caspase-3, as well as downregulation of Bcl-2 during treatment with indeno[1,2-b]quinoxalin derivatives, mediated apoptosis in human cancer cells. Arch Pharm (Weinheim). 2022;355(5):e2100454.
28. Mestrum SGC, Cremers EMP, de Wit NCJ, Drent RJM, Ramaekers FCS, Hopman AHN, et al. Integration of the Ki-67 proliferation index into the Ogata score improves its diagnostic sensitivity for low-grade myelodysplastic syndromes. Leuk Res. 2022;113:106789.
29. Vesterinen T, Saila J, Blom S, Pennanen M, Leijon H, Arola J. Automated assessment of Ki-67 proliferation index in neuroendocrine tumors by deep learning. APMIS. 2022;130(1):11-20.
30. Yan J, Xue X, Gao C, Guo Y, Wu L, Zhou C, et al. Predicting the Ki-67 proliferation index in pulmonary adenocarcinoma patients presenting with subsolid nodules: construction of a nomogram based on CT images. Quant Imaging Med Surg. 2022;12(1):642-52.
31. Wang F, Yang L, Xiao M, Zhang Z, Shen J, Anuchapreeda S, et al. PD-L1 regulates cell proliferation and apoptosis in acute myeloid leukemia by activating PI3K-AKT signaling pathway. Sci Rep. 2022;12(1):11444.
32. Wang F, Yang L, Xiao M, Zhang Z, Shen J, Anuchapreeda S, et al. PD-L1 regulates cell proliferation and apoptosis in acute myeloid leukemia by activating PI3K-AKT signaling pathway. Sci Rep. 2022;12(1):1-12.
33. Amornsupak K, Thongchot S, Thinyakul C, Box C, Hedayat S, Thuwajit P, et al. HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells. BMC Cancer. 2022;22(1):578.
34. Li J, Chen L, Xiong Y, Zheng X, Xie Q, Zhou Q, et al. Knockdown of PD-L1 in human gastric cancer cells inhibits tumor progression and improves the cytotoxic sensitivity to CIK therapy. Cell. Physiol Biochem. 2017;41(3):907-20.
| Files | ||
| Issue | Vol 22 No 5 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i5.13998 | |
| Keywords | ||
| Acute myeloid leukemia Apoptosis Cell proliferation Programmed death-ligand 1 | ||
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How to Cite
1.
Soltani M, Vosoughi M, Ganjalikhani-Hakemi M, Shapoorian H, Beshkar P, Eskandari N, Ghezelbash B. PD-1/PD-L1 Interaction Regulates BCL2, KI67, BAX, and CASP3, Altering Proliferation, Survival, and Apoptosis in Acute Myeloid Leukemia. Iran J Allergy Asthma Immunol. 2023;22(5):495-503.
